Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life's activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension, and arteriosclerosis and can contribute to elevated levels of cholesterol in the blood. It is also recognised that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness. Obesity can contribute to certain skin conditions such as atopic dermatitis and bed sores. Because overeating and obesity have become such a problem in the general population, many individuals are now interested in losing weight, reducing weight, and/or maintaining a healthy body weight and lifestyle.
Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the idea that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are targets of POMC derived peptides involved in the control of food intake and/or metabolism.
A specific, single MC-R targeted for the control of obesity has not yet been identified. To date five distinct MC-R's have been identified, and these are expressed in different tissues. MC-1R is mainly expressed in melanocytes. MC-2R is expressed in the adrenal gland. MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake and thermogenesis. MC-4R is uniquely expressed in the brain, and its inactivation was shown to cause obesity. Evidence has been presented that MC-4R signaling is important in mediating feed behavior. MC-5R is expressed in many tissues, including white fat, placenta, and exocrine glands. A low level of expression of MC-5R is also observed in the brain.
WO 00/33658 discloses methods and compositions for treating a variety of disorders associated with or caused by undesirable body weight, including obesity as well as “wasting disorders”.
WO 96/11940 discloses acyl amino acetamide derivatives with agonist activity for CCK-A receptors.
There is an on-going need for the development of a melanocortin-4 agonist useful in the treatment of obesity and other associated diseases and conditions. There is still further a need for a melanocortin-1 agonist useful in the treatment of inflammation and pain.
Accordingly, there is provided a novel group of diazepines that exhibit a useful profile of activity as agonists of the melanocortin-4 receptor and/or melanocortin-1 receptor (i.e., preferably they have MC4R and MC1R agonist activity). Novel compounds of the invention are useful in the treatment of obesity and other associated diseases and conditions.
The compounds of the invention serving as MC-1R agonists provide one or more of the following: (1) activate MC1-receptors selectively and with high potency, (2) antagonize the action of other hormones and agonists on the MC1-receptors selectively and with high potency, and/or (3) provide a method for administration of such compounds to animals, including humans. Novel compounds of the invention are disclosed showing high selectivity and high affinity for MC1-receptors in combination with effective stimulation of cAMP formation in MC1-receptor expressing cells. These compounds of the invention show low or negligible affinity for other subtypes of MC-receptors. The present invention discloses novel compounds which inhibit the production of nitric oxide (NO). Such novel diazepine compounds of the invention are melanocortin-1 agonist compounds and are thus also useful in the treatment of inflammation and pain.